tbuckley/cabot-search huggingface dataset:
Abstract 3110: Design, synthesis, and biological evaluation of transducin β-like protein 1 (TBL1) degraders
Authors: Rui Yang, Lapo Alinari, Pui-kai (Tom) Li, Xiaolin Cheng
Journal: Cancer Research (2023)

Abstract Transducin β-like protein 1 (TBL1) is an essential scaffold protein that participates in multiple critical signaling pathways, such as the Wnt/β-catenin pathway, where it protects β-catenin from ubiquitination and proteasomal degradation. Only one compound, BC-2059 (tegavivint, Iterion Therapeutics), has been reported to promote apoptosis by disrupting the TBL1/β-catenin interactions and show promising therapeutic effects in Wnt-driven cancers, such as colorectal cancer, breast cancer, and leukemia. However, recent studies showed that TBL1 modulates Wnt-regulated genes in a β-catenin-independent manner in diffuse large B-cell lymphoma (DLBCL). Although the involvement of β-catenin is still under debate, TBL1’s engagement in the antitumor effects of BC-2059 is certain and critical. In this study, we aimed to develop proof-of-concept BC-2059-based TBL1 selective degraders against DLBCL using the Proteolysis Targeting Chimeras (PROTACs) strategy and use them as chemical probes to investigate TBL1-related pathways in DLBCL. Two series (N- and O-linked) of BC-2059-based PROTACs were synthesized, and their cytotoxicity and protein degradation profiles were tested in cellular assays. Several compounds showed low micromolar to nanomolar cytotoxic activity. The TBL1 degradation of these PROTACs is currently underway. In the meantime, we modeled the ternary complex formation by developing a workflow where two binary complexes and a library of PROTACs having varied linker lengths/chemical compositions were modeled by PRosettaC. The protein-protein interactions of the generated ternary complexes were analyzed by Rosetta and the interactions between the linkers and the protein were calculated by Autodock 4. The results suggested that short linkers (8-14 heavy atoms) are more suitable for N-linked series degraders in terms of PROTAC-induced ternary complex formation, while long linkers (&amp;gt;18 heavy atoms) are preferable for O-linked series. Citation Format: Rui Yang, Lapo Alinari, Pui-kai (Tom) Li, Xiaolin Cheng. Design, synthesis, and biological evaluation of transducin β-like protein 1 (TBL1) degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3110.
Abstract 3302: KLK7 expression in human tumors: A tissue microarray study on 13,447 tumors
Authors: Simon Kind, Carolina Castillo, Ria Uhlig, Natalia Gorbokon, Maximilian Lennartz, Sebastian Dwertmann Rico, Viktor Reiswich, Florian Viehweger, Martina Kluth, Claudia Hube-Magg, Christian Bernreuther, Franziska Büscheck, Till Clauditz, Christroph Fraune, Andrea Hinsch, Till Krech, Patrick Lebok, Stefan Steurer, Eike Burandt, Sarah Minner, Andreas Marx, Ronald Simon, Waldemar Wilczak, Guido Sauter, Anne Menz, Frank Jacobsen
Journal: Cancer Research (2023)

Abstract Background: Kallikrein-related peptidase 7 (KLK7) is a chymotrypsin-like serine protease which is essential for the desquamation of corneocytes and thus plays a pivotal role in maintaining skin homeostasis. In cancer, KLK7 overexpression was suggested to represent a route for metastasis through cleavage of cell junction and extracellular matrix proteins of cancer cells. Methods: To comprehensively determine KLK7 protein expression in normal and neoplastic tissues, a tissue microarray containing 13,447 samples from 147 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results: KLK7 positivity was found in 64 of 147 tumor categories, including 17 tumor categories with at least one strongly positive case. The highest rate of KLK7 positivity was found in squamous cell carcinomas from various sites of origin (positive in 18.1%-63.8%), ovarian and endometrium cancers (4.8%-56.2%), salivary gland tumors (4.8%-13.7%), bilio-pancreatic adenocarcinomas (20.0%-40.4%), and adenocarcinomas of the upper gastrointestinal tract (3.3%-12.5%). KLK7 positivity was linked to nodal metastasis (p=0.0005), blood vessel infiltration (p=0.0037), and lymph vessel infiltration (p&amp;lt;0.0001) in colorectal adenocarcinoma, nodal metastasis in hepatocellular carcinoma (p=0.0382), advanced pathological tumor stage in papillary thyroid cancer (p=0.0132), and low grade of malignancy in a cohort of 719 squamous cell carcinomas from 11 different sites of origin (p&amp;lt;0.0001). Conclusions: These data provide a comprehensive overview on KLK7 expression in normal and neoplastic human tissues. The prognostic relevance of KLK7 expression and the possible role of KLK7 as a drug target need to be further investigated. Citation Format: Simon Kind, Carolina Castillo, Ria Uhlig, Natalia Gorbokon, Maximilian Lennartz, Sebastian Dwertmann Rico, Viktor Reiswich, Florian Viehweger, Martina Kluth, Claudia Hube-Magg, Christian Bernreuther, Franziska Büscheck, Till Clauditz, Christroph Fraune, Andrea Hinsch, Till Krech, Patrick Lebok, Stefan Steurer, Eike Burandt, Sarah Minner, Andreas Marx, Ronald Simon, Waldemar Wilczak, Guido Sauter, Anne Menz, Frank Jacobsen. KLK7 expression in human tumors: A tissue microarray study on 13,447 tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3302.
Abstract PL03-01: New insights into carcinogenesis from normal esophagus
Authors: Phil H. Jones
Journal: Cancer Research (2023)

Abstract All normal tissues studied to date carry somatic mutant clones, the burden of which increases with age. This talk considers how insights into the biology of mutants in normal tissues can inform our understanding of the earliest stages of carcinogenesis. The esophagus becomes a patchwork of mutant clones. As they expand, these clones compete for the limited space available, resulting in selection of the fittest mutant genes. The ability to out compete other mutants in normal tissue does not correlate with carcinogenic potential. For example, NOTCH1 mutant clones colonize most of the esophagus by middle age but NOTCH1 mutations are comparatively rare in squamous cancers. In mouse models Notch pathway mutant clones eliminate microscopic intraepithelial neoplasms and loss of Notch1 markedly slows esophageal tumor growth. In contrast, mutant TP53 is less effective than NOTCH1 at driving clonal expansion but is found in almost all human squamous esophageal cancers and contributes to carcinogenesis in mice. The normal tissue mutational landscape of the esophagus is shaped by environmental factors. For example, body metabolism alters the behavior of mutant PIK3CA which drives clonal expansions in the esophagus of overweight humans and mice. The mutation causes cells to switch their metabolism to aerobic glycolysis, giving the mutants a proliferative advantage. One way to reduce the competitive advantage of mutants is to increase the fitness of the neighboring cells. Treating cells or mice with metformin, a drug used to treat type 2 diabetes, induces aerobic glycolysis throughout the tissue. This eliminates the growth advantage of Pik3ca mutant clones, showing it may be possible to halt the expansion of oncogenic mutant populations. Beyond the esophagus, these findings suggest the need to consider the relative prevalence of mutations in normal tissue and the corresponding cancer(s) before deciding if a mutant gene is a cancer driver or not. Variation in cancer risk between different human populations may depend on the proportion of pro- and anti-oncogenic mutants in normal tissue. Understanding how certain mutations can impede cancer development and how environmental factors alter selection of oncogenic mutants in normal tissue may guide new approaches to cancer prevention. Citation Format: Phil H. Jones. New insights into carcinogenesis from normal esophagus. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr PL03-01.
Abstract 6088: Charting new cancer dependencies with patient derived organoids
Authors: James V. Neiswender, Lisa Brenan, Tate Bertea, Jimmy Guo, Ashley Anderson, Megan Wong, Zoe Posner, Kevin Kapner, Connor Hennessey, Sarah Wie, Isabella Boyle, Barbara De Kegel, Joshua Dempster, Yuen-Yi (Moony) Tseng, David Root, Andrew Aguirre, Francisca Vazquez
Journal: Cancer Research (2023)

Abstract The number of patients benefiting from precision cancer medicine (PCM) is very limited. The Cancer Dependency Map Initiative aims to dramatically accelerate PCM by systematically identifying the landscape of cancer vulnerabilities across all tumors. Genome-wide knockout screens have been performed in over 1000 cancer cell lines, but these have been sourced from historically derived models, leaving many cancers underrepresented. Advances have been made in model derivation by growing cells in 3D formats, such as organoids or spheroids. These models present an opportunity to screen new cancer types, but come with challenges that require a new pipeline. Here, we present a set of screens using a genome wide CAS12 library in organoid tumor models representing novel subtypes of pancreatic, esophageal, and gastric cancer, along with treatment-resistant breast, ovarian, and prostate cancer organoids. We show that genome-wide screening of these models is feasible and can be achieved with quality comparable to 2D cell lines. Our work uncovered a set of novel dependencies associated with cell-ECM interactions that have not previously been identified in 2D models. Our methods provide a framework for screening future patient derived 3D culture models and discovering vulnerabilities in new tumor types. Citation Format: James V. Neiswender, Lisa Brenan, Tate Bertea, Jimmy Guo, Ashley Anderson, Megan Wong, Zoe Posner, Kevin Kapner, Connor Hennessey, Sarah Wie, Isabella Boyle, Barbara De Kegel, Joshua Dempster, Yuen-Yi (Moony) Tseng, David Root, Andrew Aguirre, Francisca Vazquez. Charting new cancer dependencies with patient derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6088.
Abstract 4759: Dissecting EP300 and CBP function in prostate cancer models
Authors: Kiran Mirpuri, Alok K. Tewari, Myles A. Brown
Journal: Cancer Research (2023)

Abstract Prostate adenocarcincoma is dependent on androgen and its cellular receptor the androgen receptor (AR) for most of the natural history of the disease including progression to the advanced and lethal state. Many prostate cancer therapeutics target the androgen signaling pathway, although tumors invariably become resistant to these treatments. EP300 and CBP are protein paralogs that are co-regulators of AR-mediated gene transcription and are mutated at low frequency in prostate cancers. Expression of CBP and EP300 has been found to correlate with AR expression in advanced disease, and their inhibition can impact AR-mediated transcription in model systems. However, both proteins are not equally essential in prostate cancer cell lines. As drugs inhibiting the bromodomains of these proteins are in early clinical trials, a greater understanding of the common and unique functions of EP300 and CBP may inform the clinical application of these therapeutics. Using chemical inhibition or degradation of either each paralog or both, in combination with genetic depletion, we identify converging and diverging epigenomic and transcriptional programs regulated by each paralog both in the presence and absence of androgens. If validated in tumor samples from patients, these results may nominate biomarkers of response to EP300/CBP inhibitors. Citation Format: Kiran Mirpuri, Alok K. Tewari, Myles A. Brown. Dissecting EP300 and CBP function in prostate cancer models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4759.
Abstract 4191: Assessing performance of biomarker extraction from electronic health records: Data augmentation methods for a hierarchical self-attention network (HiSAN)
Authors: Shalini Priya, Alina Peluso, Mayanka Chandra Shekhar, Ioana Danciu, Jordan Miller, Heidi A. Hanson
Journal: Cancer Research (2023)

Abstract Background: Extraction of HER2 status from electronic health records (EHR) may expedite clinical trials matching and be used for survivorship research. Deep learning (DL) algorithms have potential to extract this data; however, inherent class imbalance leads to reduced model performance. We compare state of the art strategies to handle class imbalance in models trained to extract HER2 status. This comparative analysis may be used as a guideline for HER2 extraction. Methods: 680,117 pathology reports collected from 2017-2021 by the National Cancer Institutes’ Surveillance, Epidemiology, and End-Results (SEER) program were used for this study. Pathology reports are manually labelled by cancer registrars as HER2 -, HER2+, or Unknown (class ratio 65%, 11%, 24% respectively). We compare six data augmentation (DA) methods: balanced frequency weighting, ROS while up-sampling HER2+ by 595%, RUS while down-sampling HER2- by 83%, SMOTE, ADASYN, and SMOTE-Tomek. As a comparison we consider the HiSAN model i.e., a DL architecture currently used by SEER for automatic classification of reports. Result: Applying DA strategies did not improve the performance of the HiSAN model (Table 1). Frequency based class-weighting (Acc=0.78), ROS (Acc=0.81), and RUS (Acc=0.80) perform worse than the baseline model, suggesting simple data augmentation methods do not boost performance for this task. Advanced oversampling with SMOTE (Acc=0.88) and ADASYN (Acc=0.88) perform better than simple approaches, but do not improve the predictive accuracy of the baseline HiSAN. Conclusion: Common DA methods do not improve the performance of the HiSAN biomaker method. While the overall accuracy of the baseline HiSAN model is quite high, other methods for improved accuracy should be explored. Table 1. Method Accuracy (Acc) Sensitivity Specificity Precision HiSAN (Baseline) 0.8898 0.7583 0.8944 0.8507 Frequency class weighting 0.7826 0.8033 0.8932 0.7040 Random Over Sampling (ROS) 0.8057 0.7672 0.8883 0.7130 Random Under Sampling (RUS) 0.8042 0.7883 0.8930 0.6902 Synthetic Minority Oversampling Technique (SMOTE) 0.8796 0.7341 0.8827 0.8340 Adaptive Synthetic Sampling (ADASYN) 0.8764 0.7467 0.8863 0.8142 SMOTE-Tomek 0.8823 0.7620 0.8956 0.8200 Citation Format: Shalini Priya, Alina Peluso, Mayanka Chandra Shekhar, Ioana Danciu, Jordan Miller, Heidi A. Hanson. Assessing performance of biomarker extraction from electronic health records: Data augmentation methods for a hierarchical self-attention network (HiSAN). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4191.
Abstract 4016: Discovery of a small-molecule EGFR inhibitor that can potently target various EGFR mutants, including C797S mutant, in vitro and in vivo
Authors: Yeejin Jeon, Kiram Lee, Anna Jang, Miyeon Kim, Kyeong Jin Yoon, Yeri Lee, Dongsu Kim, Donggeon Kim, Dohyun Park, Sang Kyun Lim, Sung Pil Choi
Journal: Cancer Research (2023)

Abstract EGFR is one of receptor tyrosine kinases (RTKs) and, upon ligand binding, turns on the downstream signals that include oncogenic RAS/MEK/ERK, PI3K/AKT/mTOR, and JAK/STAT pathways. EGFR gene mutations, such as Exon 19 deletion (Del19) and L858R mutations, induce abnormal activation of the EGFR protein even in the absence of the ligand leading to various cancers. EGFR mutations are found in non-small cell lung cancer (NSCLC) patients with 10-15% frequency (approximately 50% in Asian patients). Starting from Del19 and L8585R mutations, additional mutations in the EGFR gene occur during the treatment with 1st/2nd/3rd generation EGFR inhibitors, resulting in Del19/T790M, L858R/T790M, Del19/T790M/C797S, L858R/T790M/C797S, Del19/C797S, and L858R/C797S mutations. While double mutations that include the T790M mutation have been efficaciously treated with Osimertinib, there are currently no approved therapies that can effectively target the C797S-containing mutants. Here we present preclinical data showing a small-molecule inhibitor that effectively disables EGFR mutants, including Del19/T790M/C797S, L858R/T790M/C797S, Del19/C797S, and L858R/C797S mutants. High potency and selectivity were confirmed by in vitro kinase assays and cellular assays. Outstanding anti-cancer activity was observed in mouse xenograft models with various EGFR mutations and, importantly, it was inactive in the EGFR wild-type model. With confirmed brain penetrance through in vivo studies, our potent EGFR inhibitor may provide a great therapeutic potential for patients with EGFR mutation-driven NSCLC. Citation Format: Yeejin Jeon, Kiram Lee, Anna Jang, Miyeon Kim, Kyeong Jin Yoon, Yeri Lee, Dongsu Kim, Donggeon Kim, Dohyun Park, Sang Kyun Lim, Sung Pil Choi. Discovery of a small-molecule EGFR inhibitor that can potently target various EGFR mutants, including C797S mutant, in vitro and in vivo. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4016.
Abstract 2940: Use of NK humanized mouse models for the <i>in vivo</i> evaluation of anti-tumor NK-cell therapies
Authors: Pauline Rettman, Laure-Marie Meyer, Ravi Rangara, Anna Ponchet-Lac, Nicolas Moindrot, Angélique Biancotto, Céline Lefranc, Fabien Delahaye, Emilia Rabia, Matteo Cesaroni, Sukhvinder Sidhu, Céline Nicolazzi
Journal: Cancer Research (2023)

Abstract Novel immunotherapeutic strategies targeting human Natural Killer (huNK) cells using monoclonal or multi-specific antibodies and immune modulator molecules are under development and there is a pressing need to have suitable mouse models for the evaluation of these therapeutics. Existing humanized mouse models have limitations and do not show an optimal development of innate immune cells such as NK, dendritic or other myeloid cells. We previously described the development of robust mouse models that allow the engraftment and maintenance of fully functional huNK cells using several strains of immunodeficient transgenic mice for human cytokines (IL-15). The optimal parameters (source of immune cells, pre-conditioning regimen, route of administration) were identified, and the models were validated by flow cytometry and in vivo efficacy studies using an anti-CD20 Ab. Here, we report further development and characterization of these models and highlight their value to evaluate a variety of NK based therapeutics. We show that huNK cells can infiltrate a subcutaneous B-cell lymphoma model after treatment with an anti-CD20 Ab. We show that SAR444245 (non-alpha IL2) can activate huNK cells in vivo in all developed huIL-15 transgenic models and confirmed the minimal effective dose by flow-cytometry PD studies. We show the efficacy of both reference and internal ADCC-enhanced antibodies in disseminated tumor models in our humanized huIL-15 transgenic mice. In addition, we performed a deep characterization of huNK cells in huIL-15 transgenic models, using a 28-color flow cytometry panel centered on NK cell biology and profiled them transcriptionally by single cell RNA Seq in a disseminated B-cell lymphoma model. Overall, we have developed robust models sustaining fully functional huNK cells that can be proficiently recruited in vivo by various NK-based therapeutics and can be used to evaluate the efficacy of combination therapies. Citation Format: Pauline Rettman, Laure-Marie Meyer, Ravi Rangara, Anna Ponchet-Lac, Nicolas Moindrot, Angélique Biancotto, Céline Lefranc, Fabien Delahaye, Emilia Rabia, Matteo Cesaroni, Sukhvinder Sidhu, Céline Nicolazzi. Use of NK humanized mouse models for the in vivo evaluation of anti-tumor NK-cell therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2940.
Abstract 4771: Prevention of doxorubicin-induced cardiotoxicity by benfotiamine
Authors: Justin R. Taylor, Kyra Harames
Journal: Cancer Research (2023)

Abstract Anthracyclines such as daunorubicin and doxorubicin (DOX) are currently used as chemotherapeutic agents in the prevention of various cancers including breast cancer, lung cancer, leukemia, and lymphoma. Although, anthracyclines are successful in controlling various cancers growth, the major drawback is the unwanted cardiotoxicity. Specifically, high doses of DOX used for the therapy of advanced cancers could cause life threating conditions. Therefore, specific interventions are required to decrease the cardiac toxicity associated with the DOX. Benfotiamine, a lipid soluble vitamin B1 derivative has shown be a potent anti-oxidant and anti-inflammatory agent. However, the efficacy of benfotiamine in the prevention of cardiotoxicity associated with the anthracyclines is not known. In this study, we examined the effect of benfotiamine in the prevention of DOX-induced cytotoxicity in the human umbilical vascular endothelial cells (HUVECs). Treatment of HUVECs with DOX caused significant endothelial cells death and benfotiamine in a concentration-dependent manner prevented the dox-induced endothelial cell death. Further, benfotiamine prevents the DOX-induced apoptosis in endothelial cells by preventing the activation of caspase-3. Benfotiamine also prevents DOX-induced reactive oxygen species generation. Our results also indicate that benfotiamine regulates DOX-induced expression of pro-apoptotic mediators such as BAD, phosphor-P53, and pro-caspase-3, and anti-apoptotic mediators such as BCL-2, BCL-x, IAPs, and HSP and others such as FADD, DR5, and SMAC/diablo. We plan to further explore how benfotiamine prevents DOX-induced cardiotoxicity using human cardiac myocytes and mouse models. Thus, based on our cell culture studies, benfotiamine through its potent anti-oxidative property could prevent endothelial cytotoxicity and suggests that it could be further developed as adjuvant therapy in controlling cardiotoxicity associated with the anthracycline chemotherapy. Citation Format: Justin R. Taylor, Kyra Harames. Prevention of doxorubicin-induced cardiotoxicity by benfotiamine. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4771.